The migration of leukocytes through the body and the various lymphoid organs is an essential element of the immune system. While circulating in blood or lymphatic vessels, leukocytes are in a resting and low adhesive state. However, when leukocytes are stimulated by signals from the immune system such as exposure to an immune complex or a chemokine gradient, their integrin adhesion receptors become activated. The activation of the integrins is essential for the many functions of leukocytes.
Such functions are, for example, binding to antigen-presenting cells, recirculation through lymph nodes and migration out of the vasculature and through the extracellular matrix to sites of inflammation. The integrin activation needs to be tightly regulated as inappropriate leukocyte adhesion leads to significant injury of normal tissues.
Leukocytes express a specific subset of the integrin family, the β2 integrins of which four members are currently known. They have a common β2 chain (CD 18) but different α subunits (αL/CD11a, αM/CD11b, αx/CD 11c, and αD/CD11d) (Gahmberg et al., 1997, Eur. J. Biochem 245:215-232). The α subunits contain a conserved 200-residue A or I domain, which is essential for binding of most ligands. The crystal structures of I domains from the αL and αM subunits indicate the presence of a cation binding site called the metal ion-dependent adhesion site (MIDAS). Amino acid substitutions in this site abrogate ligand binding (Huang and Springer, 1995, J. Biol. Chem. 270:19008-19016; Kamata et al., 1995, J. Biol. Chem. 270, 12531-12535).
The major ligands of these integrins, the ICAMs, belong to the immunoglobulin superfamily, and five ICAMs with slightly different binding specificities have been described. The expression of ICAM-1 on endothelial cells is subject to stimulation by inflammatory cytokines, which enhances the β2 integrin-mediated adhesion of leukocytes on endothelial cells. LFA-1 dependent ICAM-1 stimulation has been implicated in leukocyte adhesion, aggregation and transendothelial migration.
Inhibition of LFA-1/ICAM-1 binding has potential therapeutic benefits relating to blocking allograft rejection, including cardiac, renal and thryoid allografts (Isobe et al., Science, 255:1125, 1992; Stepkowski et al., 1994, J Immunol., 144:4604; Cosimi et al., 1990, J. Immunol, 144:4604; Nakakura et al., 1993, Transplantation, 55:412; Talento et al., Transplantation, 55:418, 1993), bone marrow transplants (Tibbetts et al., Transplantation, 68:685, 1999; Cavazzana-Calvo et al., Transplantation, 59:1576, 1995) T-cell mediated sensitization reactions (Ma et al., Cell Immunol., 15:389, 1994; Cumberbatch et al., Arch. Dermatol. Res., 288:739, 1996), diabetes (Hasegawa et al., Int. Immunol., 6:831, 1994), rheumatoid arthritis (Davis et al., J. Immunol., 154:3525, 1995; Kavanaugh et al., Arthritis Rheum., 37:992, 1994), and artherosclerosis (Kawamura et al. Circ J 68:6-10, 2004). Expression of ICAM-1 by keratinocytes is also implicated in the etiology of psoriasis, and inhibition of LFA-1/ICAM-1 binding presents a possible point of therapeutic intervention (Servitje et al., J. Cutan. Pathol., 23:431, 1996). Thus the peptide compositions of the present invention may be used in treatment of the above conditions and more generally in any condition T-cell mediated condition wherein T-cells are activated via interaction of LFA-1 and ICAM-1.
Because of the importance of integrins and their ligands for leukocyte function and associated diseases, antagonists of integrin-ligand binding will provide significant therapeutic benefit.